Rohit Mehra1, Pankaj Vats2, Xuhong Cao3, Fengyun Su4, Nicole D Lee5, Robert Lonigro4, Kumpati Premkumar3, Kiril Trpkov6, Jesse K McKenney7, Saravana M Dhanasekaran4, Arul M Chinnaiyan8. 1. Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. 2. Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Science, School of Basic Medical Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India. 3. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, Ann Arbor, MI, USA. 4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. 5. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. 6. Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada. 7. Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, OH, USA. 8. Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, Ann Arbor, MI, USA. Electronic address: arul@med.umich.edu.
Abstract
Renal cell carcinomas (RCC) with overlapping histomorphologic features poses diagnostic challenges. This is exemplified in RCCs with eosinophilic cytoplasm that include eosinophilic solid and cystic RCC (ESC RCC), RCCs in germline aberrations of tuberous sclerosis complex (TSC) genes mutated (TSC RCC) individuals, and other RCC subtypes. We used next-generation sequencing (NGS) technology to molecularly profile seven ESC RCC tumors. Mutational and copy number analysis of NGS data revealed mutually exclusively somatic bi-allelic loss of TSC1 or TSC2 genes-both negative regulators of the mammalian target of rapamycin (mTOR) pathway in 85% (6/7) of evaluated cases. Thus, lack of germline TSC aberration in matched non-neoplastic renal parenchyma distinguishes ESC RCC from TSC RCC. Immunohistochemistry data shows mTOR pathway activation in all tumors, thus supporting a pathognomonic role for TSC aberrations in ESC RCC. Our study clarifies the molecular identity of ESC RCC, provides basis for the revision of current RCC classification, and may guide future therapeutic strategies. PATIENT SUMMARY: Molecular characterization of eosinophilic solid and cystic renal cell carcinomas (ESC RCC) revealed recurrent and mutually exclusive somatic homozygous loss of tuberous sclerosis complex family genes. This observation provides greater insight into the unique biology of this novel type of tumor and potentially expands the therapeutic options for ESC RCC patients.
Renal cell carcinomas (RCC) with overlapping histomorphologic features poses diagnostic challenges. This is exemplified in RCCs with eosinophilic cytoplasm that include eosinophilic solid and cystic RCC (ESC RCC), RCCs in germline aberrations of tuberous sclerosis complex (TSC) genes mutated (TSC RCC) individuals, and other RCC subtypes. We used next-generation sequencing (NGS) technology to molecularly profile seven ESC RCC tumors. Mutational and copy number analysis of NGS data revealed mutually exclusively somatic bi-allelic loss of TSC1 or TSC2 genes-both negative regulators of the mammalian target of rapamycin (mTOR) pathway in 85% (6/7) of evaluated cases. Thus, lack of germline TSC aberration in matched non-neoplastic renal parenchyma distinguishes ESC RCC from TSC RCC. Immunohistochemistry data shows mTOR pathway activation in all tumors, thus supporting a pathognomonic role for TSC aberrations in ESC RCC. Our study clarifies the molecular identity of ESC RCC, provides basis for the revision of current RCC classification, and may guide future therapeutic strategies. PATIENT SUMMARY: Molecular characterization of eosinophilic solid and cystic renal cell carcinomas (ESC RCC) revealed recurrent and mutually exclusive somatic homozygous loss of tuberous sclerosis complex family genes. This observation provides greater insight into the unique biology of this novel type of tumor and potentially expands the therapeutic options for ESC RCC patients.
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